Project Summary: Better therapeutic approaches are needed to attain the Healthy People 2010 objectives 25-4 and 25-10 of reducing genital herpes infection and its consequences in neonates. Understanding how herpes simplex virus type 2 (HSV-2) evades the host's immune system is a critical step toward the development of improved therapies for genital and neonatal herpes. The long-term goal of the Candidate is to develop an independent research career as an infectious disease clinician scientist focused on the immunology of herpesvirus infections. The objective of this application is to determine how HSV-2 induces apoptosis in T cells. Since T cells are recruited to control HSV at the site of recurrence, we predict that induction of T cell apoptosis is an integral immune evasion mechanism during reactivation of viral infection. This application focuses on HSV-2 because it is the major etiologic agent of genital and neonatal herpes. The central hypothesis is that key viral proteins of HSV-2 induce apoptosis in T cells by increasing expression of pro-apoptotic genes. Guided by the Candidate's previous work, this hypothesis will be tested by pursuing two specific aims: 1) Identification of HSV-2 gene products that are required to induce apoptosis in T cells;and 2) Determination of the cellular components of apoptosis pathways in T cells that are modulated by HSV-2. The proposed research is significant because it provides the knowledge base needed to disrupt an immune evasion mechanism used by the virus, while providing the means to establish the Candidate's independence as a physician-scientist. The Candidate's training and research experience to date, coupled with having identified a well-established mentor, helps to assure that the scientific and training goals of this application will be met. Relevance to Public Health: This is an important area of herpes simplex virus immunology that seeks to identify the viral immune evasion mechanisms important for reactivation of genital and neonatal infections. This work has potential applicability in developing novel therapies to reduce public health consequences from virus reactivation in genital and neonatal infections.